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J Biol Chem. 2004 Feb 20;279(8):6824-33. Epub 2003 Nov 21.

The Kindler syndrome protein is regulated by transforming growth factor-beta and involved in integrin-mediated adhesion.

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  • 1Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah 84112-5550, USA.


Transforming growth factor-beta1 (TGF-beta1) contributes to tumor invasion and cancer progression by increasing the motility of tumor cells. To identify genes involved in TGF-beta-mediated cell migration, the transcriptional profiles of human mammary epithelial cells (HMEC) treated with TGF-beta were compared with untreated cells by cDNA microarray analysis. One gene up-regulated by TGF-beta was recently named kindlerin (Jobard, F., Bouadjar, B., Caux, F., Hadj-Rabia, S., Has, C., Matsuda, F., Weissenbach, J., Lathrop, M., Prud'homme, J. F., and Fischer, J. (2003) Hum. Mol. Genet. 12, 925-935). This gene is significantly overexpressed in some cancers (Weinstein, E. J., Bourner, M., Head, R., Zakeri, H., Bauer, C., and Mazzarella, R. (2003) Biochim. Biophys. Acta 1637, 207-216), and mutations in this gene lead to Kindler syndrome, an autosomal-recessive genodermatosis. TGF-beta stimulation of HMEC resulted in a marked induction of kindlerin RNA, and Western blotting demonstrated a corresponding increase in protein abundance. Kindlerin displays a putative FERM (four point one ezrin radixin moesin) domain that is closely related to the sequences in talin that interact with integrin beta subunit cytoplasmic domains. The critical residues in the talin FERM domain that mediate integrin binding show a high degree of conservation in kindlerin. Furthermore, kindlerin is recruited into a molecular complex with the beta1A and beta3 integrin cytoplasmic domains. Consistent with these biochemical findings, kindlerin is present at focal adhesions, sites of integrin-rich, membrane-substratum adhesion. Additionally, kindlerin is required for normal cell spreading. Taken together, these data suggest a role for kindlerin in mediating cell processes that depend on integrins.

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